Resveratrol affects hepatic gluconeogenesis via histone deacetylase 4

Purpose: The aim of this study was to determine whether resveratrol (Rev) affects the expression, phosphorylation, and nuclear and cytoplasmic distribution of histone deacetylase 4 (HDAC4), which in turn affects gluconeogenesis in hepatocytes under an insulin-resistant state. Materials and methods: HepG2 cells were treated with 0.25 mmol/L palmitic acid (PA) to establish an insulin resistance model. The cells were divided into five groups: control, PA, PA + Rev 100 mu M, PA + Rev 50 mu M, and PA + Rev 20 mu M. After treatment for 24 hours, mRNA and protein expression levels of gluconeogenesis pathway-related molecules and HDAC4 were examined. Next, HepG2 cells were transfected with siRNA-HDAC4. The cells were divided into control, PA, PA + Rev 20 mu M, PA + Rev 20 mu M + siRNA-HDAC4 negative control, and PA + Rev 20 mu M + siRNA-HDAC4 knockdown groups to determine the expression of gluconeogenesis pathway proteins. Results: Compared with the control group, the gluconeogenesis pathway-related molecules, glucose-6-phosphatase catalytic subunit (G6PC), phosphoenolpyruvate carboxykinase 1 (PCK1) and forkhead box protein O1 (FOXO1), were increased, and the phosphorylation of FOXO1 decreased after PA treatment. The p-HDAC4 level decreased with the increase in HDAC4 in the nucleus and the decrease in HDAC4 in the cytoplasm in the PA group. Treatment with Rev 20 mu M suppressed gluconeogenesis and promoted HDAC4 shuttling into the cytoplasm from the nucleus. However, 100 and Rev 50 mu M exerted the opposite effects. Finally, after HDAC4 knockdown, the expression levels of the key gluconeogenesis molecules, G6PC, PCK1, and FOXO1, were increased, and p-FOXO1 was decreased, indicating that gluconeogenesis was enhanced. Conclusion: A low concentration of Rev inhibited gluconeogenesis under insulin-resistance conditions via translocation of HDAC4 from the nucleus to the cytoplasm.